Aromatic aldehydes are prepared by two primary synthetic methods: a direct method which consists of attaching a CHO group onto an aromatic derivative, and an indirect method which consists of oxidizing a group which is already present on the aromatic derivative. There are several well known methods for electrophilically formylating aromatic compounds containing activating (electron-donating) substituents, but these fail completely or are impractical for aromatic compounds which contain electron withdrawing substituents such as fluorine. To overcome this dilemma, new synthetic processes are continually being developed.
A direct formylation method is disclosed within U.S. Pat. No. 4,588,844 to Kysela et al., which describes a reaction between an aromatic compound and urotropine (hexamethylenetetramine, HMT) in a hydrofluoric acid medium. Yields obtained for compounds such as fluorobenzene were rather low (about 30%) and are not suitable for industrial utilization.
Another direct formylation method is disclosed within by U.S. Pat. No. 5,068,450 to Crochemore et al., which discloses a process consisting of reacting methyl formate with an aromatic derivative in liquid hydrofluoric acid in the presence of boron trifluoride. Yields of fluorobenzaldehyde obtained by incorporating fluorobenzene in this process are high (about 85%) and reportedly give a single isomer, 4-fluorobenzaldehyde. U.S. Pat. No. 5,138,099 to Lang also discloses a direct formylation procedure in which a fluorinated aromatic derivative (fluorobenzene, 2-fluorotoluene) is reacted with dichloromethyl methyl ether in methylene chloride in the presence of ferric chloride. Isomeric impurities are then selectively removed by halogenation with bromine. Although high isomeric purities are claimed, the use of toxic intermediates such as dichloromethyl methyl ether and an expensive halogenating agent such as bromine make this process unsuitable for industrial utilization.
Other methods for preparing fluorinated benzaldehydes are known which use halogen-exchange (HALEX) chemistry (Journal of Fluorine Chemistry 46, 529-537 (1990). This method involves the reaction of chlorinated benzaldehydes with a metal halide, usually potassium fluoride, in a polar solvent to give a fluorinated benzaldehyde. Since only halogens in "activated" positions (those ortho and para to a formyl group) undergo halogen-exchange, the scope of this method is somewhat limited.
Aromatic formylation has traditionally been performed, since its development in the late 1800s, by a Gattermann-Koch procedure which comprises the reaction of the aromatic derivative with carbon monoxide, hydrogen chloride, and an appropriate catalyst (usually aluminum chloride). This standard reaction required the combination of equivalent amounts of aluminum chloride, carbon monoxide, and gaseous hydrogen chloride reacted in the presence of a substituted benzene. The temperature was controlled from 25 to 50.degree. C., and the pressure was kept at 1,000 psig. Such a reaction yielded about 70% of the desired substituted benzaldehyde; however, the utilization of gaseous HCl and the need for high reaction pressures are highly undesireable from a safety standpoint. Modifications of the Gattermann-Koch reaction have been developed for specific monoalkyl-substituted benzaldehydes, such as in U.S. Pat. No. 4,622,429 to Blank et al. and di- and trialkyl-subsituted benzaldehydes in U.S. Pat. No. 4,195,040 to Renner.
While Gattermann-Koch chemistry works extremely well to prepare benzaldehyde, monoalkyl-, and polyalkyl-benzaldehydes, its use in preparing fluorinated benzaldehydes has gone virtually unexplored. Only one example is known whereby a fluorinated benzaldehyde was obtained from Gatternann-like conditions (Journal of Practical Chemistry 135, 101-127 (1932); C.A. 27, 713). In this example 3-fluoro-4-ethoxybenzaldehyde was obtained in 40% yield from the reaction of 1-fluoro-2-ethoxybenzene with zinc cyanide, hydrogen chloride, and aluminum chloride.
Even with these methods, there still remains a need in the art for methods of synthesizing fluorinated benzaldehydes in high isomeric purity and in a commercially viable manner that does not use highly toxic, corrosive, and costly reagents.